Associations of preoperative anaemia with healthcare resource use and outcomes after colorectal surgery: a population-based cohort study

Background Preoperative anaemia is common in patient undergoing colorectal surgery. Understanding the population-level costs of preoperative anaemia will inform development and evaluation of anaemia management at health system levels. Methods This was a population-based cohort study using linked, routinely collected data, including residents from Ontario, Canada, aged ≥18 yr who underwent an elective colorectal resection between 2012 and 2022. Primary exposure was preoperative anaemia (haemoglobin <130 g L−1 in males; <120 g L−1 in females). Primary outcome was 30-day costs in 2022 Canadian dollars (CAD), from the perspective of a publicly funded healthcare system. Secondary outcomes included red blood cell transfusion, major adverse events (MAEs), length of stay (LOS), days alive at home (DAH), and readmissions. Results We included 54,286 patients, with mean 65.3 (range 18–102) years of age and 49.0% females, among which 21 264 (39.2%) had preoperative anaemia. There was an absolute adjusted cost increase of $2671 per person at 30 days after surgery attributable to preoperative anaemia (ratio of means [RoM] 1.05, 95% confidence interval [CI] 1.04–1.06). Compared with the control group, 30-day risks of transfusion (odds ratio [OR] 4.34, 95% CI 4.04–4.66), MAEs (OR 1.14, 95% CI 1.03–1.27), LOS (RoM 1.08, 95% CI 1.07–1.10), and readmissions (OR 1.16, 95% CI 1.08–1.24) were higher in the anaemia group, with reduced DAH (RoM 0.95, 95% CI 0.95–0.96). Conclusions Approximately $2671 CAD per person in 30-day health system costs are attributable to preoperative anaemia after colorectal surgery in Ontario, Canada.


Editor's key points
Anaemia is now widely recognised to be an important risk factor for poor perioperative outcomes.However, it is unclear whether correcting anaemia before, during, and after surgery reduces the risk of poor outcomes.The evidence base for interventions such as blood transfusion and i.v.iron is complex and does not present a clear case for routine perioperative correction of anaemia.The current study estimates the additional healthcare costs of perioperative treatments required for treatment of preoperative anaemia.These findings suggest that, if proven clinically effective, treating preoperative anaemia would also be cost-effective in the perioperative period.
Preoperative anaemia is present in more than 40% of patients undergoing colorectal surgery, and is known to be associated with poor outcomes, including higher rates of mortality, complications, length of stay (LOS), and readmissions.1e6 A study using National Surgical Quality Improvement Program data demonstrated an increased associated risk of acute renal failure, stroke, myocardial infarction, and death (odds ratio [OR] 1.49e2.19), with a doseeresponse relationship between anaemia severity and these outcomes. 1,7,8espite this growing evidence, multifactorial barriers to preoperative anaemia optimisation exist.First, healthcare providers are not always aware of the importance of preoperative anaemia and its association with poor outcomes. 2,9dditionally, perioperative care, including anaemia optimisation, requires collaborative efforts from various practitioners such as primary care physicians, anaesthesiologists, perioperative care physicians, and surgeons.The lack of clearly defined roles among the patient's circle of care in managing and monitoring anaemia may often lead to its oversight. 10,11Data supporting the effectiveness of preoperative anaemia management are also uncertain.For example, a multicentre trial involving 487 participants did not find evidence of reduced red blood cell (RBC) transfusion with administration of i.v.iron therapy in anaemic abdominal surgery patients (risk ratio [RR] 0.98, 95% confidence interval [CI] 0.68e1.43). 12However, this trial was underpowered, may have lacked ideal alignment of its intervention to anaemia aetiology in all participants, and faced challenges in timely delivery of iron therapy.Thus, these data do not preclude the possibility that i.v.iron therapy and other interventions aimed at anaemia management could provide benefit.Finally, the paucity of data on the economic impact of preoperative anaemia may also be a barrier to development of effective management strategies. 2,13nderstanding the resource use and outcome burden attributable to anaemia at a population level could help prioritise development of effective anaemia management strategies and inform economic evaluation of perioperative blood management (PBM) programmes.We conducted a populationbased cohort study to estimate the association of preoperative anaemia with health system costs and clinical outcomes in adult patients undergoing elective colorectal surgery.

Design and setting
After protocol registration (https://doi.org/10.17605/OSF.IO/ A586T), we conducted a population-based, retrospective cohort study in Ontario, Canada, where all residents have access to healthcare through the provincial health insurance.In Ontario, standardised methods are used to collect and store linked healthcare data at ICES (formerly known as the Institute for Clinical Evaluative Sciences).The dataset was prepared and analysed by a trained data analyst and is reported following recommended methods (Supplementary Appendix I). 14,15The study was legally waived from research ethics review per provincial health privacy legislation.

Cohort
Ontario residents aged !18 yr who underwent elective colorectal resection between April 1, 2012 and March 31, 2022 were identified for inclusion.The Canadian Classification of Intervention codes for colon and rectal resections were used to identify eligible patients (Supplementary Appendix II), which have demonstrated validity. 16The cohort was limited to 1) elective surgeries only, as emergency patients would not have time for optimisation of haemoglobin concentrations before surgery and 2) an individual's first surgery if they received multiple surgeries within the study period.

Exposure
The primary exposure was anaemia as defined by the World Health Organization's (WHO) guidelines (Hgb <130 g L À1 in males, <120 g L À1 in females). 17We evaluated the haemoglobin value most proximal to surgery between 90 days and 1 day before surgery to avoid misclassification of an intraoperative or postoperative value.Secondary representations of haemoglobin (that were not sex dependent) included a continuous linear, restricted cubic spline to allow for a continuous, but potentially nonlinear association, and categorical representation of WHO severity (not anaemic, mild [110 g L À1 normal], moderate [80 to <110 g L À1 ], and severe [<80 g L À1 ]). 17

Outcome
The primary outcome was total healthcare costs at 30 days (i.e.costs starting from the day of surgery to postoperative day 29) from the perspective of the universal public healthcare system.Costs were normalised to 2022 Canadian dollars (CAD) and were calculated using validated patient-level costing algorithms that include direct and non-direct medical costs associated with all patient contacts with the healthcare system (Supplementary Appendix III). 18This method does not account for production costs of RBC units, which are paid for by Canadian Blood Services, and out-of-pocket patient expenses.
Secondary outcomes included health system costs in the 90 and 365 days after surgery, in-hospital major adverse events [MAEs] (composite of major cardiac and renal complications or death), LOS, receipt of any RBC transfusion, 30-day readmissions, and days alive at home.Specific details and diagnostic codes are listed in Supplementary Appendix IV.

Confounders
Potential confounders were selected based on clinical and epidemiological knowledge of factors that we postulated Cost of anaemia in colorectal surgery -59 would be associated with anaemia and dependent variables (Supplementary Appendix V).These included patient characteristics, Elixhauser comorbidities, frailty index score, total health system costs accrued in the year before surgery, the specific surgical procedure, receipt of chemotherapy in the 6 months before surgery, estimated glomerular filtration rate, presence of a cancer tissue diagnoses of colon or rectal cancer before surgery, and presence of inflammatory bowel disease. 19,20

Sample size
As a population-based study, we planned to include all patients who underwent colorectal surgery from 2012 to 2022.With an estimate that at least 4000 colorectal procedures are performed annually in Ontario and existing data demonstrating mean case costs of $20,000 CAD (standard deviation [SD] $23,000), we determined that we would require a minimum of 1119 participants for a linear regression model with an explained variance of 0.2.21e24

Missing data
As 22.3% of exposure data were missing, we followed our prespecified approach using multiple imputation to create 25 complete datasets based on Rubin's rules. 25Predictive mean matching via multivariate chained equations (MICE) was used to impute missing haemoglobin values directly, under a missing at random assumption.There were no complete gaps in haemoglobin testing across time or centre.However, there were greater percentage of missing data in the earlier years of the observation period.For instance, 26.1% of the missing haemoglobin values were from 2012, 19.7% from 2013, 14.5% from 2014, 10.6% from 2015, with percentages of missing data from each year decreasing thereafter.This might be owing to increasing awareness for the importance of preoperative anaemia detection.Further information on the diagnostics for multiple imputation can be found in Supplementary Appendix VIaec.

Data analysis
Descriptive statistics were calculated comparing characteristics between people with and without preoperative anaemia.Standardised differences were calculated to identify differences that may be substantive (i.e.standardised difference >0.10). 26Unadjusted and adjusted outcome differences between exposure levels were analysed using generalised linear models.In addition to the exposure variable, all adjusted models included control for pre-specified confounders while accounting for clustering by hospital using generalised estimating equations.Cost and LOS were modelled using logtransformed values in a linear model; binary outcomes were modelled using logistic models; days alive at home was modelled using the negative-binomial regression.For primary cost outcomes, the adjusted model's predicted values were used to generate adjusted absolute differences and CIs computed via bootstrapped standard errors of 200 replicates. 27

Sensitivity analysis
Pre-specified sensitivity analyses were conducted using representations of anaemia and haemoglobin concentration that were not sex dependent.Specifically, the primary analysis was re-run with a continuous, then a continuous nonlinear (restricted cubic spline) of haemoglobin concentration, then the four-level WHO anaemia severity categorisation as exposure variables.Post hoc, we re-ran the primary model with days alive during the 30-day window as an offset to account for the impact of early mortality on cost accumulation, and an analysis that accounted for estimated transfusion costs (as our data did not capture the costs of RBC units transfused (Supplementary Appendix VII).

Effect modification
Effect modifier analyses using multiplicative interaction terms between binary exposure and the following factors were conducted: oncologic vs benign surgical indication; cancer stage (limited to patients with colorectal cancer); frailty index score; age; sex; neighbourhood income quintiles.We also conducted effect modifier analyses using interaction terms of continuous haemoglobin with sex and age.P-values <0.05 were considered significant for interaction.

Results
Figure 1 demonstrates the patient flow diagram for inclusion and analysis.Overall, 69,904 patients undergoing elective colorectal surgery in Ontario between 2012 and 2022 were included; 54,286 (77.7%) had complete exposure data.Among these, 21,264 (39.2%) had preoperative anaemia, 35,108 (64.7%) patients had a colorectal cancer diagnosis, and 2167 (4.0%) patients had inflammatory bowel disease.Patients with anaemia were older, lived with greater frailty, tended to have more comorbidities, and were more likely to have a cancer indication for surgery than those without anaemia (Table 1).Baseline characteristics of the study population with and without complete exposure data can be seen in Supplementary Table S1.

Sensitivity analyses
Complete case analyses were consistent with the primary analysis.All parameterisations of anaemia demonstrated significantly increased adjusted costs for patients with anaemia, lower haemoglobin concentrations, or both.When parameterised as a four-level categorical variable with nonsex-dependent thresholds, anaemia demonstrated stepwise increases in attributable costs relative to patients without anaemia (Fig. 2).As a continuous variable, each 10 g L À1 increase in haemoglobin was associated with mean cost decrease of 1% (aRoM 0.99, 95% CI 0.98e0.99).As a nonlinear continuous restricted cubic spline, decreasing costs were associated with increasing haemoglobin concentration with an inflection point at 130 g L À1 .This pattern was consistent at 90 and 365 days (Supplementary Appendix VIII).After adding estimated transfusion-attributable costs (Supplementary Appendix VII), the adjusted RoM was similar to the results of the primary analysis (aRoM 1.05, 95% CI 1.05e1.07)with mean absolute adjusted cost difference of $2879 (95% CI $2870e$2889).Accounting for survival time, anaemia was significantly associated with increased costs (RoM 1.03, 95% CI 1.02e1.04).

Effect modification
Figure 3 provides a summary of pre-specified binary and categorical effect modification analyses.No significant effect modification was identified by sex (P¼0.77) or cancer status (P¼0.12).Significant effect modification was identified by income quintiles (P¼0.01), and among cancer patients by tumour stage (P<0.001).When continuous terms were analysed, those with greater frailty experienced a steady decrease in anaemiaattributable relative cost increase, which was statistically significant up to a frailty index score of 0.3 (Supplementary Appendix IXa).Although anaemic patients experienced significant cost increases across age range, the association peaked at age 55 years and demonstrated a nadir at age 75 years, with minimal difference in the RoM between the two ages at 30 days (Supplementary Appendix IXb).The interaction of continuous haemoglobin concentration with sex demonstrated that females had lower mean costs across haemoglobin concentration up to 166 g L À1 (Supplementary Appendix IXc).

Discussion
In a population-based, retrospective cohort study of adult patients undergoing elective colorectal surgery in Ontario, preoperative anaemia was significantly associated with an adjusted cost increase of $2672 CAD per person in the 30 days after surgery.This association was consistent across sensitivity analyses that involved differing assumptions and representations of preoperative haemoglobin concentration.Preoperative anaemia was also significantly associated with increased rates of adverse clinical outcomes, including transfusion, LOS, readmissions, and reduced days alive at home.These findings can inform the possible value and economic benefits of future efforts aimed at anaemia management.
Robust estimates of costs attributable to preoperative anaemia are lacking. 2Given the high prevalence, precise estimates of attributable costs are crucial to understand the impact of preoperative anaemia on resource-constrained healthcare systems and estimate the value of potentially expensive processes and interventions such as PBM programmes and i.v.iron therapies.To date, a single-centre study of 851 elective colorectal surgery patients estimated that preoperative anaemia was associated with an increase of $3027 CAD (95% CI $2664e$3397) in index hospitalisation costs. 2 Our study estimated a similar degree of attributable costs over the first 30 postoperative days ($2671 CAD [95% CI $2661e$2680]) while adjusting for a more robust set of confounders and capturing all costs across a universal healthcare system.Cost differences continued to increase at 90 and 365 days, which could suggest that the clinical and subsequently, health system impacts of anaemia become more pronounced over time.28e30 However, interpretation of outcomes that are temporally farther away from the date of surgery and factor of study (i.e.preoperative anaemia) are limited. 31naemia in colorectal surgery is more prevalent with higher attributable costs than in other surgical populations including orthopaedic (12% prevalence, V426 or ~$600 CAD in total joint arthroplasty) and gynaecologic (23% prevalence, $865 CAD in hysterectomy) surgery.32e34 Although hysterectomies are limited to biologically female individuals only, the observed higher costs in colorectal surgery do not appear to be related to sex differences, as our analyses did not identify sex as an effect modifier.Instead, the higher cost difference in colorectal surgery may be attributable to the inclusion of complex cancer cases and the greater physiologic stress of colorectal surgery leading to higher rates of postoperative complications. 35In our analyses, higher stage of cancer (stage 0eIV) was identified as an effect modifier among patients with cancer.In contrast, the presence of any cancer across all colorectal surgery patients was not.Although seemingly counterintuitive, this result likely reflects at least two factors.
First, the analysis of cancer stage was limited to those in our cohort with a cancer diagnosis (i.e. a different risk set from the full population), and second, most cancers were less advanced, which might have diluted the effect of cancer in the full population.
Developing efficacious and cost-effective strategies to manage preoperative anaemia must remain a priority, especially given the population-level and societal impact of anaemia on the healthcare system.In Ontario, with a population of 14 million people, we estimate that anaemia contributed to more than $56 million in health system spending across the 10 yr of our study, or more than $5.5 million per year.As iron-deficiency anaemia secondary to gastrointestinal bleeding is a major aetiological factor for preoperative anaemia in colorectal surgery populations, strategies to address anaemia have typically included preoperative iron supplementation.Unfortunately, existing studies reveal complexities that may limit the effectiveness of this approach.Specifically, the multicentre PRE-VENTT trial involving 487 patient assessed the efficacy of a single i.v.iron therapy on anaemic patients undergoing major abdominal surgery.This study did not find evidence of reduced transfusion risk (RR 0.98, 95% CI 0.68e1.43)or adverse outcomes (RR 0.89, 95% CI 0.52e1.55).Nonetheless, substantial opportunities still exist to optimise anaemia treatment, informed in part by the PREVENTT trial. 12For example, although a  Forest plot comparing primary analysis with sensitivity analysis (SA) estimates of binary and categorical exposures.For each association, the figure reports the ratio of means (large circle) and 95% confidence interval comparing mean costs between those with vs without anaemia (unless otherwise indicated).
Cost of anaemia in colorectal surgery -63 pragmatic 'one-size-fits-all' approach may not be ideal, multidisciplinary PBM programmes that stress clinician awareness, differentiation of common causes, and institution of early therapy may be more effective in improving outcomes and reducing costs; however, appropriately powered randomised trials are still warranted. 2,7,8,36ur study features several strengths and limitations.Although our population-based design should support generalisability to similar populations and health systems, we cannot estimate generalisability to substantively different jurisdictions.In particular, for countries with much higher or lower absolute healthcare costs, our estimate of absolute attributable cost increase may not be relevant, and readers should prefer our relative estimates, while also considering the similarities and differences between delivery of surgical care in Canada and elsewhere.The internal validity of our findings should also be considered, including protocol preregistration, use of validated measures of exposure, outcomes, and patient-level costing algorithms, and control for a robust set of confounders.Pre-planned sensitivity analyses supported the consistency and robustness of our findings, including concordance between our primary analysis using multiple imputation to account for missing exposure data and complete case analysis, suggesting that missing data were non-differential.It is also crucial that readers recognise that our study did not test or compare any interventions to treat or correct preoperative anaemia, so we are unable to draw any direct conclusions about cost-effectiveness.As the strength of attribution between an exposure measured before surgery and outcomes measured after surgery is expected to weaken over time, especially if unmeasured mediators or time-varying covariates emerge, interpretation of 90-and 365-day costs should be done with caution.Unfortunately, we could not identify the aetiology of anaemia, limiting our ability to explore aetiologic effect modification.Additionally, we used thresholds for anaemia according to the WHO definitions (i.e.<120 g L À1 in women and <130 g L À1 in men).Some experts suggest that haemoglobin <130 g L À1 should be considered anaemia, regardless of sex. 37As we used the WHO definitions, we might have captured more severe cases of anaemia in Forest plot of effect modification analyses for the association of anaemia and cost at 30 days.For each association, the figure reports the ratio of means (large circle) and 95% confidence interval comparing mean costs between those with vs without anaemia.Effect modifiers that were significant at the 5% level were cancer stage (among patients with cancer) and neighbourhood income quintile.women leading to overestimated effects; had a single threshold for anaemia been used, our estimates might have been slightly different. 13However, in sensitivity analyses we found no effect modification by sex.Furthermore, the cost outcome was limited to the perspective of a publicly funded healthcare system in Ontario, Canada.Therefore, societal costs (i.e.loss of individual economic productivity, informal care costs from family members) and out-of-pocket expenses from patients (i.e.costs of travel) were not captured.

Conclusions
In patients undergoing adult colorectal surgery, we estimate that the presence of anaemia before surgery is associated with increased costs of $2672 CAD (aROM 1.05, 95% CI 1.04e1.06),and significantly increased rates of adverse clinical and patient-centred outcomes in the 30 days after surgery.These data highlight the substantial impact of anaemia on colorectal surgery patients and the healthcare system.Efficacious and cost-effective interventions and processes are needed to inform management of perioperative anaemia, which remains prevalent in colorectal surgery patients.

Fig 2 .
Fig 2. Forest plot comparing primary analysis with sensitivity analysis (SA) estimates of binary and categorical exposures.For each association, the figure reports the ratio of means (large circle) and 95% confidence interval comparing mean costs between those with vs without anaemia (unless otherwise indicated).

Fig 3 .
Fig 3. Forest plot of effect modification analyses for the association of anaemia and cost at 30 days.For each association, the figure reports the ratio of means (large circle) and 95% confidence interval comparing mean costs between those with vs without anaemia.Effect modifiers that were significant at the 5% level were cancer stage (among patients with cancer) and neighbourhood income quintile.

Table 1
Baseline characteristics of study population.eGFR, estimated glomerular filtration rate.**absolute standardized differences >0.1 represent a substantial difference.

Table 2
Costs associated with anaemia status.SD, standard deviation; RBC, red blood cell.*All costs are in 2022 adjusted Canadian dollars; y Adjusted covariates: age, sex, neighbourhood income quintile, rural vs urban residence, Elixhauser comorbidities, presence of colon or rectal cancer tissue diagnosis, frailty index score, preoperative healthcare resource utilisation, the specific surgical procedure, receipt of chemotherapy in the 6 months before surgery, estimated glomerular filtration rate, and presence of inflammatory bowel disease.

Table 3
Effect estimates for secondary outcomes with respect to preoperative anaemia status.CI, confidence interval; RBC, red blood cell.*Estimation unit reported as odds ratio.y Estimation unit reported as ratio of means.z Adjusted covariates: age, sex, neighbourhood income quintile, rural vs urban residence, Elixhauser comorbidities, presence of colon or rectal cancer tissue diagnosis, frailty index score, preoperative healthcare resource utilisation, the specific surgical procedure, receipt of chemotherapy in the 6 months before surgery, estimated glomerular filtration rate, and presence of inflammatory bowel disease.